A systematic review and meta-analysis of pro-dopaminergic interventions for anhedonia - results from human studies

1. Methods (brief)

In this first iteration of the living systematic review we searched for randomised controlled trials that compared pro-dopaminergic interventions to placebo in adults with unipolar depression (i.e. any standardised measure, above-threshold symptoms on any standardised measure, or a clinical diagnosis based on any operationalised criteria).

Eight databases were searched from inception up to the 9th of November, 2023 (see protocol for full search strings). Database search results were imported into EPPI-Reviewer and de-duplicated prior to screening. All steps related to record screening and data extraction were completed in EPPI-Reviewer.

Titles and abstracts of the identified records were screened by at least two reviewers (CF, MC, JK, JP). We retrieved the full-texts and any supporting documents for all records that were not excluded at the title and abstract screening stage. The full-text screening was conducted by at least two reviewers (CF, JK, JP, AK, EB). Conflicts at title and abstract, and full-text screening, were resolved through discussion between the two reviewers and involvement of a third reviewer (AC, EGO). Additional information on the full study eligibility criteria can be found in the pre-published protocol.

Relevant data was extracted using EPPI-Reviewer by at least two reviewers (CF, CA, EB, JK).

As specified in our protocol, we focused on:

• anhedonia symptom severity: using anhedonia-specific scales, anhedonia-specific sub-scales, or individual items focusing on anhedonia (observer-rated or self-rated). Continuous, primary outcome.
• acceptability: proportion of participants dropping out for any reason. Binary, secondary outcome.
• tolerability: the proportion of participants dropping out due to an adverse event. Binary, secondary outcome.
• safety: the proportion of participants reporting specific adverse events. Binary, secondary outcome.
• anxiety symptom severity: as per observer or self-reported standardised scales. Continuous, secondary outcome.

For anhedonia and anxiety symptom severity, we extracted outcome data reported at 8 weeks post-treatment or manipulation. If the information at 8 weeks was not available, we considered eligible data ranging between 4 and 12 weeks (with preference to the time point closest to 8 weeks and, if equidistant, the longer outcome). For acceptability, tolerability, safety and safety (specific adverse events), we extracted outcome data reported at the end of the studies.

When extracting continuous outcomes we extracted mean and standard deviation to two decimal places. Where standard error was reported instead, we converted the value to standard deviation. Baseline and endpoint values were extracted, where only change in score and baseline or endpoint was reported, the missing value was calculated by adding or subtracting the change score to the baseline or endpoint.

When extracting dichotomous outcomes we extracted natural numbers and where only percentages of participant groups were reported, a value was calculated and rounded up to the nearest natural number. Adverse events were extracted using the exact terms they were reported in the included studies.

We assessed risk of bias with the RoB2 tool (Higgins et al. 2019). All outcomes for all included studies were assessed by at least two reviewers (JK, CF, CA, AH) and conflicts were resolved by discussion between reviewers (Flemyng et al, 2023). To evaluate biases due to missing evidence and biases across studies, the ROB-ME tool (Page et al, 2023) was used with the same double screening and conflict resolution process as described above.

Effect sizes were calculated as standardised mean differences (SMDs) for continuous outcomes (anhedonia and anxiety symptom severity) and odds ratios (ORs) for dichotomous outcomes (acceptability, tolerability, and specific-adverse events). We calculated the 95% confidence interval (CI) around the pooled effect size for each meta-analysis.

Meta-analyses were conducted using a random effects model with the inverse variance method, using the restricted maximum-likelihood estimator for tau² and the Q-Profile method for the confidence interval of tau². Confidence intervals were adjusted using the Hartung-Knapp method. Prediction intervals were calculated to better report the effect of heterogeneity on the overall pooled effect.

We conducted a series of sensitivity analyses on the primary outcome. We aggregated individual participant data (IPD) of randomised controlled trials on antidepressants in people with depression, performing a series of random effects network meta-analyses to compare the effects of pro-dopaminergic and non-pro-dopaminergic pharmacological interventions on anhedonia.

Subgroup analyses and meta-regressions were also conducted for the following variables: mean age of participants, mean anhedonia baseline score, mean anxiety baseline score, sex (proportion of female participants), and planned treatment duration. This was done using a mixed-effects model with the estimation of the between-study heterogeneity tau² based on the REML method. Meta-regressions were only conducted for outcomes where data was available from 10 or more studies.

Summary of evidence tables were constructed for all outcomes including a summary of the meta-analytic result, biases within-study, across-study, and due to indirectness.

Please refer to the protocol and the extended data for more details.

A list of abbreviations can be found towards the end of the document.

2. Results

2.1 Flow diagram

Figure 1. PRISMA 2020 flow diagram (Page et al 2021).

Back to top

2.2 Table of included studies

Author (Year)	Country	Sponsor	Eligible arms	Setting	Condition	Treatment duration	Intervention group	Participants (n)	Females (n)	Age (mean)	Age (SD) or range (specified)	Dosage fixed or flexible	Intervention format	Planned dosage range (min-max mg/day)	Delivered dosage range (min-max mg/day)	Delivered dosage (mean mg/day)
Agosti (1991)	USA	NA	3	Secondary/Tertiary Care	Non melancholic chro*c depression	6 weeks	Phenelzine	10	NA	NA	NA	Flexible	Oral	60mg to 90mg	NA	NA
Agosti (1991)	USA	NA	3	Secondary/Tertiary Care	Non melancholic chro*c depression	6 weeks	Placebo	23	NA	NA	NA	Flexible	Oral	NA	NA	NA
Agosti (1991)	USA	NA	3	Secondary/Tertiary Care	Non melancholic chro*c depression	6 weeks	Selegiline	12	NA	NA	NA	Fixed	Oral	40mg	40mg	NA
Amsterdam (1989)	USA	Sanofi Research (partial grant)	5	NA	Major depression	4 weeks	Minaprine 100mg	34	12	41	12	Flexible	Oral	100mg to 400mg	NA	93mg
Amsterdam (1989)	USA	Sanofi Research (partial grant)	5	NA	Major depression	4 weeks	Minaprine 200mg	39	25	37	13	Flexible	Oral	100mg to 400mg	NA	186mg
Amsterdam (1989)	USA	Sanofi Research (partial grant)	5	NA	Major depression	4 weeks	Minaprine 300mg	43	22	40	12	Flexible	Oral	100mg to 400mg	NA	279mg
Amsterdam (1989)	USA	Sanofi Research (partial grant)	5	NA	Major depression	4 weeks	Minaprine 400mg	37	22	37	13	Flexible	Oral	100mg to 400mg	NA	352mg
Amsterdam (1989)	USA	Sanofi Research (partial grant)	5	NA	Major depression	4 weeks	Placebo	37	18	39	13	NA	Oral	NA	NA	NA
Amsterdam (2003)	USA	Somerset Pharmaceuticals, Inc.	2	Secondary/Tertiary Care	Major depressive disorder, single or recurrent episode	8 weeks	Selegiline	149	94	41.2	11.6	Fixed	Transdermal	20mg	20mg	NA
Amsterdam (2003)	USA	Somerset Pharmaceuticals, Inc.	2	Secondary/Tertiary Care	Major depressive disorder, single or recurrent episode	8 weeks	Placebo	152	99	43.5	10	Fixed	Transdermal	NA	NA	NA
Bakish (1992)	Canada	NA	2	NA	Major depressive episode	6 weeks	Moclobemide	58	26	42	10.9	Flexible	Oral	NA to 600mg	NA to 600mg	492mg
Bakish (1992)	Canada	NA	2	NA	Major depressive episode	6 weeks	Placebo	56	20	44	10.7	Flexible	Oral	NA	NA	NA
Bellak (1966)	USA	*MH	2	Secondary/Tertiary Care	Depression	4 weeks	Placebo	25	NA	NA	NA	NA	NA	NA	NA	NA
Bellak (1966)	USA	*MH	2	Secondary/Tertiary Care	Depression	4 weeks	Phenelzine	25	NA	NA	NA	NA	NA	NA	NA	NA
Benes (2011)	Germany	GSK	2	NA	At least mild depressive symptoms	12 weeks	Placebo	67	45	59.5	11.3	Flexible to week 7, then fixed	Oral	NA	NA	NA
Benes (2011)	Germany	GSK	2	NA	At least mild depressive symptoms	12 weeks	Ropinirole	198	144	58.2	11.4	Flexible to week 7, then fixed	Oral	0.5 mg to 4 mg	NA	1.9 mg
Bodkin (2002)	NA	Somerset Pharmaceuticals	2	Secondary/Tertiary Care	Major depressive disorder, single or recurrent episode	6 weeks	Placebo	88	53	43.2	10.8	Fixed	Transdermal	NA	NA	NA
Bodkin (2002)	NA	Somerset Pharmaceuticals	2	Secondary/Tertiary Care	Major depressive disorder, single or recurrent episode	6 weeks	Selegiline	89	53	41.4	10.9	Fixed	Transdermal	20mg	20mg	20mg
Botte (1992)	NA	NA	2	NA	Unipolar depression, neurotic depression	6 weeks	Placebo	24	16	43.33	9.9	NA	NA	NA	NA	NA
Botte (1992)	NA	NA	2	NA	Unipolar depression, neurotic depression	6 weeks	Moclobemide	23	13	51.39	12.69	Flexible	Oral	300mg to 600mg	200mg to 600mg	NA
Bymaster (2011)	Romania, Serbia, USA	DOV Pharmaceuticals, Euthymics Bioscience	2	Secondary/Tertiary Care	Depressive disorder	6 weeks	Placebo	29	19	49.5	6.9	Fixed	Oral	NA	NA	NA
Bymaster (2011)	Romania, Serbia, USA	DOV Pharmaceuticals, Euthymics Bioscience	2	Secondary/Tertiary Care	Depressive disorder	6 weeks	Amitifadine	34	25	48.2	9.4	Fixed	Oral	50mg to 50mg	25mg to 50mg	NA
Casacchia (1984)	Italy	NA	2	Secondary/Tertiary Care	Unipolar psychotic depression, neurotic depression	4 weeks	Moclobemide	18	8	49.5	12.8	Flexible	Oral	NA	150mg to 450mg	297.2mg
Casacchia (1984)	Italy	NA	2	Secondary/Tertiary Care	Unipolar psychotic depression, neurotic depression	4 weeks	Placebo	16	11	49	11.4	Flexible	Oral	NA	150mg to 400mg	212.5mg
Chouinard (1993)	Canada, UK	NA	2	Secondary/Tertiary Care	Major depressive episode	6 weeks	Placebo	109	66	40.200000000000003	18-64 (range)	Fixed	Oral	NA	NA	NA
Chouinard (1993)	Canada, UK	NA	2	Secondary/Tertiary Care	Major depressive episode	6 weeks	Brofaromine	111	57	41.2	18-64 (range)	Fixed	Oral	75mg to 150mg	NA	NA
Coleman (1999)	USA	Glaxo Wellcome Inc.	2	NA	Moderate to severe depression	8 weeks	Placebo	124	73	38.5	18-65 (range)	Flexible	Oral	NA	NA	NA
Coleman (1999)	USA	Glaxo Wellcome Inc.	2	NA	Moderate to severe depression	8 weeks	Bupropion SR	122	68	38.1	18-64 (range)	Flexible	Oral	150mg to 400mg	100mg to 365mg	290mg
Coleman (1999)	USA	Glaxo Wellcome Inc.	2	NA	Moderate to severe depression	8 weeks	Placebo	152	92	36.700000000000003	19-62 (range)	Flexible	Oral	NA	NA	NA
Coleman (1999)	USA	Glaxo Wellcome Inc.	2	NA	Moderate to severe depression	8 weeks	Bupropion	150	95	36.6	18-67 (range)	Flexible	Oral	150mg to 400mg	NA	NA
Corrigan (2000)	USA	NA	4	NA	Major depression, single episode or recurrent episode	8 weeks	Placebo	35	NA	NA	NA	Fixed	Oral	NA	NA	NA
Corrigan (2000)	USA	NA	4	NA	Major depression, single episode or recurrent episode	8 weeks	Pramipexole 0.375mg	36	NA	NA	NA	Fixed	Oral	0.375mg	0.375mg	0.375mg
Corrigan (2000)	USA	NA	4	NA	Major depression, single episode or recurrent episode	8 weeks	Pramipexole 1mg	35	NA	NA	NA	Fixed	Oral	1mg	1mg	1mg
Corrigan (2000)	USA	NA	4	NA	Major depression, single episode or recurrent episode	8 weeks	Pramipexole 5mg	33	NA	NA	NA	Fixed	Oral	5mg	5mg	5mg
Croft (1999)	NA	Glaxo Wellcome Inc.	2	NA	Moderate to severe depression	8 weeks	Placebo	121	61	37.4	19-64 (range)	Flexible	Oral	NA	NA	NA
Croft (1999)	NA	Glaxo Wellcome Inc.	2	NA	Moderate to severe depression	8 weeks	Bupropion SR	120	61	35.9	19-70 (range)	Flexible	Oral	150mg to 400mg	127mg to 361mg	293mg
Davidson (1988)	NA	Hoffmann La Roche	2	NA	Major or minor depression	6 weeks	Isocarboxazid	68	37	41.9	NA	Flexible	Oral	NA	NA	49.3mg
Davidson (1988)	NA	Hoffmann La Roche	2	NA	Major or minor depression	6 weeks	Placebo	62	35	41.9	NA	Flexible	Oral	NA	NA	NA
DelBello (2014)	USA	Somerset Pharmaceutical, Inc.	2	Secondary/Tertiary Care	Moderate or severe Major Depressive Disorder	12 weeks	Placebo	156	104	14.7	1.6	Flexible	Transdermal	NA	NA	NA
DelBello (2014)	USA	Somerset Pharmaceutical, Inc.	2	Secondary/Tertiary Care	Moderate or severe Major Depressive Disorder	12 weeks	Selegiline	152	93	14.8	1.62	Flexible	Transdermal	6mg to 12mg	NA	NA
Feiger (2006)	USA	Somerset Pharmaceutical, Inc.	2	NA	Moderate or severe Major Depressive Disorder	8 weeks	Selegiline	132	81	42	NA	Flexible	Transdermal	6mg to 12mg	6mg to 12mg	NA
Feiger (2006)	USA	Somerset Pharmaceutical, Inc.	2	NA	Moderate or severe Major Depressive Disorder	8 weeks	Placebo	133	71	42	NA	Flexible	Transdermal	NA	NA	NA
Feighner (1984)	NA	NA	2	Secondary/Tertiary Care	Major depressive disorder	4 weeks	Placebo	22	19	49	22-78 (range)	NA	Oral	NA	NA	NA
Feighner (1984)	NA	NA	2	Secondary/Tertiary Care	Major depressive disorder	4 weeks	Bupropion	44	30	43.9	20-70 (range)	Flexible	Oral	NA to 600mg	300mg to 600mg	392mg
Georgotas (1986)	USA	NAMH	2	NA	Major depressive disorder	7 weeks	Placebo	28	15	64.7	7.6	Flexible	Oral	NA	NA	NA
Georgotas (1986)	USA	NAMH	2	NA	Major depressive disorder	7 weeks	Phenelzine	22	13	65.5	4.4000000000000004	Flexible	Oral	NA	NA	53.90mg
Giller (1982)	USA	NAMH, Hoffman-LaRoche	2	Secondary/Tertiary Care	Depression	6 weeks	Placebo	NA	NA	NA	NA	Flexible	Oral	NA	NA	73mg
Giller (1982)	USA	NAMH, Hoffman-LaRoche	2	Secondary/Tertiary Care	Depression	6 weeks	Isocarboxazid	NA	NA	NA	NA	Flexible	Oral	NA	NA	48mg
GlaxoSmithKline (1980)	USA	GSK	3	Community	Major depressive disorder	6 weeks	Bupropion 150-450mg	52	35	36.4	21-67 (range)	Flexible	Oral	150mg to 450mg	NA	NA
GlaxoSmithKline (1980)	USA	GSK	3	Community	Major depressive disorder	6 weeks	Bupropion 300-900mg	23	13	37.799999999999898	21-62 (range)	Flexible	NA	300mg to 900mg	NA	NA
GlaxoSmithKline (1980)	USA	GSK	3	Community	Major depressive disorder	6 weeks	Placebo	47	31	37.4	21-60 (range)	Flexible	Oral	NA	NA	NA
GlaxoSmithKline (1985)	USA, Canada	GSK	3	Secondary/Tertiary Care	Depressive disorder	4 weeks	Placebo	43	20	51.9	25-78 (range)	Fixed	Oral	NA	NA	NA
GlaxoSmithKline (1985)	USA, Canada	GSK	3	Secondary/Tertiary Care	Depressive disorder	4 weeks	Bupropion 300mg	45	18	52.4	26-80 (range)	Fixed	Oral	300mg	300mg	NA
GlaxoSmithKline (1985)	USA, Canada	GSK	3	Secondary/Tertiary Care	Depressive disorder	4 weeks	Bupropion 450mg	40	18	47.5	20-73 (range)	Fixed	Oral	450mg	450mg	NA
GlaxoSmithKline (1993)	USA	GSK	5	NA	NA	8 weeks	Placebo	124	80	40.700000000000003	11.6	NA	NA	NA	NA	NA
GlaxoSmithKline (1993)	USA	GSK	5	NA	NA	8 weeks	Bupropion SR 100mg	119	77	39.6	11.9	Fixed	NA	100mg	NA	NA
GlaxoSmithKline (1993)	USA	GSK	5	NA	NA	8 weeks	Bupropion SR 200mg	120	65	39.6	10.4	Fixed	NA	200mg	NA	NA
GlaxoSmithKline (1993)	USA	GSK	5	NA	NA	8 weeks	Bupropion SR 300mg	120	70	39.9	11.4	Fixed	NA	300mg	NA	NA
GlaxoSmithKline (1993)	USA	GSK	5	NA	NA	8 weeks	Bupropion SR 400mg	119	66	38.799999999999898	11.7	Fixed	NA	400mg	NA	NA
GlaxoSmithKline (1994)	USA	GSK	3	Secondary/Tertiary Care	Major depressive disorder	8 weeks	Bupropion 50-150mg	152	90	39.1	12.2	Flexible	Oral	50mg to 150mg	50mg to 150mg	NA
GlaxoSmithKline (1994)	USA	GSK	3	Secondary/Tertiary Care	Major depressive disorder	8 weeks	Placebo	154	99	38.200000000000003	11.4	NA	Oral	NA	NA	NA
GlaxoSmithKline (1994)	USA	GSK	3	Secondary/Tertiary Care	Major depressive disorder	8 weeks	Bupropion 100-300mg	150	98	37.200000000000003	11.3	Flexible	Oral	100mg to 300mg	100mg to 300mg	NA
Han (2012)	South Korea	Korea Research Foundation Grant	2	Community	MDD and problematic online game play	8 weeks	Placebo	28	0	18.100000000000001	6.2	NA	NA	NA	NA	NA
Han (2012)	South Korea	Korea Research Foundation Grant	2	Community	MDD and problematic online game play	8 weeks	Bupropion	29	0	21.2	8	Fixed	Oral	150mg to 300mg	NA	NA
Hewett (2009)	Austria, Belgium, Bulgaria, Croatia, Estonia, Finland, Greece, Ireland, Latvia, Netherlands, Poland, Portugal, Russia, Slovakia, Spain, Sweden and Mexico	GSK	2	NA	Major depressive disorder	8 weeks	Placebo	199	142	41.8	11.56	Flexible	Oral	NA	NA	NA
Hewett (2009)	Austria, Belgium, Bulgaria, Croatia, Estonia, Finland, Greece, Ireland, Latvia, Netherlands, Poland, Portugal, Russia, Slovakia, Spain, Sweden and Mexico	GSK	2	NA	Major depressive disorder	8 weeks	Bupropion XR 150-300mg	188	138	41.8	11.68	Flexible	Oral	150mg to 300mg	NA	170.1mg
Hewett (2010a)	Australia, France, Germany, the Netherlands, Norway, South Africa and Sweden	GSK	2	NA	Major depressive disorder	8 weeks	Placebo	189	125	44.5	10.79	Flexible	Oral	NA	NA	NA
Hewett (2010a)	Australia, France, Germany, the Netherlands, Norway, South Africa and Sweden	GSK	2	NA	Major depressive disorder	8 weeks	Bupropion XR	204	127	45.6	11.76	Flexible	Oral	150mg to 300mg	150mg to 300mg	180mg
Hewett (2010b)	Australia, Belgium, Canada, Croatia, Finland, France, Germany, India, Latvia, Netherlands, Norway, Poland, Republic of South Africa, Russia and United States	GSK	2	NA	Major depressive disorder	10 weeks	Placebo	207	144	71.3	5.9	Flexible	Oral	NA	NA	NA
Hewett (2010b)	Australia, Belgium, Canada, Croatia, Finland, France, Germany, India, Latvia, Netherlands, Norway, Poland, Republic of South Africa, Russia and United States	GSK	2	NA	Major depressive disorder	10 weeks	Bupropion XR	211	157	70.900000000000006	5.6	Flexible	Oral	150mg to 300mg	150mg to 300mg	NA
Iosifescu (2022)	USA	Xsome Therapeutics	2	NA	Major depressive disorder	6 weeks	Dextromethorphan + Bupropion	156	95	42.1	12.8	NA	Oral	45mg to 105mg	NA	NA
Iosifescu (2022)	USA	Xsome Therapeutics	2	NA	Major depressive disorder	6 weeks	Placebo	162	117	41.2	13.77	NA	Oral	NA	NA	NA
Jarrett (1999)	NA	NA	2	Community	Major depressive disorder, atypical features	10 weeks	Phenelzine	36	25	38.700000000000003	9.7799999999999905	NA	NA	0.85mg/kg to 1mg/kg	NA	64mg
Jarrett (1999)	NA	NA	2	Community	Major depressive disorder, atypical features	10 weeks	Placebo	36	22	40.299999999999898	10.08	NA	NA	NA	NA	NA
Jefferson (2006)	NA	GSK	2	NA	Major depressive disorder	8 weeks	Placebo	139	96	39.799999999999997	16-69 (range)	Flexible	Oral	NA	NA	NA
Jefferson (2006)	NA	GSK	2	NA	Major depressive disorder	8 weeks	Bupropion XR	135	89	40	20-68 (range)	Flexible	Oral	150mg to 450mg	150mg to 450mg	NA
Koshino (2013)	Japan, South Korea	GSK	3	NA	Major depressive disorder	10 weeks	Placebo	186	85	37.9	11.09	Fixed	Oral	NA	NA	NA
Koshino (2013)	Japan, South Korea	GSK	3	NA	Major depressive disorder	10 weeks	Bupropion 150mg	190	92	36	10.42	Fixed	Oral	150mg	150mg	NA
Koshino (2013)	Japan, South Korea	GSK	3	NA	Major depressive disorder	10 weeks	Bupropion 300mg	188	83	37.5	10.96	Fixed	Oral	300mg	300mg	NA
Kusalic (1993)	NA	NA	2	NA	Major depressive episode	6 weeks	Placebo	9	NA	NA	NA	Flexible	Oral	NA	NA	NA
Kusalic (1993)	NA	NA	2	NA	Major depressive episode	6 weeks	Moclobemide	11	NA	NA	NA	Flexible	Oral	NA	NA	482.60mg
Larsen (1989)	Denmark	NA	2	Secondary/Tertiary Care	Major depressive episode	6 weeks	Placebo	18	12	57	25-76 (range)	Flexible	Oral	NA	NA	NA
Larsen (1989)	Denmark	NA	2	Secondary/Tertiary Care	Major depressive episode	6 weeks	Moclobemide	22	15	51	28-70 (range)	Flexible	Oral	NA to 300mg	NA to 300mg	NA
Learned (2012a)	Australia, Belgium, Bulgaria, Canada, Estonia, Finland, France, Germany, India, Poland, Slovakia, and South Africa	GSK	2	NA	Major depressive disorder	10 weeks	Placebo	126	46	41.9	11.79	Fixed	Oral	NA	NA	NA
Learned (2012a)	Australia, Belgium, Bulgaria, Canada, Estonia, Finland, France, Germany, India, Poland, Slovakia, and South Africa	GSK	2	NA	Major depressive disorder	10 weeks	GSK372475	134	51	43	12.07	Fixed	Oral	1.5mg to 2mg	1mg to 2mg	NA
Learned (2012b)	Bulgaria, Canada, Chile, Costa Rica, Croatia, France, Germany, India, Italy, and Poland	GSK	2	NA	Major depressive disorder	10 weeks	Placebo	156	39	41.8	10.89	Fixed	Oral	NA	NA	NA
Learned (2012b)	Bulgaria, Canada, Chile, Costa Rica, Croatia, France, Germany, India, Italy, and Poland	GSK	2	NA	Major depressive disorder	10 weeks	GSK372475	171	54	42.4	11.64	Fixed	Oral	1mg to 1.5mg	1mg to 1.5mg	NA
Liebowitz (1984)	NA	Public Health Service	2	Community	Atypical depression	6 weeks	Placebo	24	14	37.700000000000003	8.9	Flexible	Oral	NA	NA	NA
Liebowitz (1984)	NA	Public Health Service	2	Community	Atypical depression	6 weeks	Phenelzine	15	7	33.799999999999898	9.3000000000000007	Flexible	Oral	15mg to 90mg	60mg to 90mg	74mg
Mann (1989)	USA	Irma Hirschl and Mallinckrodt Foundations	2	Secondary/Tertiary Care	Major depressive episode	6 weeks	Placebo	22	17	40.200000000000003	10.7	Flexible	NA	NA	NA	NA
Mann (1989)	USA	Irma Hirschl and Mallinckrodt Foundations	2	Secondary/Tertiary Care	Major depressive episode	6 weeks	Selegiline	22	16	45.2	12.3	Flexible	Oral	NA	NA to 50mg	NA
Nair (1995)	Canada, Denmark, UK	NA	2	Secondary/Tertiary Care	Major depressive episode	7 weeks	Moclobemide	36	25	67 (median)	60-90 (range)	Fixed	Oral	400mg	400mg	NA
Nair (1995)	Canada, Denmark, UK	NA	2	Secondary/Tertiary Care	Major depressive episode	7 weeks	Placebo	35	25	71 (median)	62-89 (range)	Fixed	Oral	NA	NA	NA
Ose (1992)	NA	NA	2	NA	Major depressive episode	4 weeks	Moclobemide	35	21	49 (median)	24-79 (range)	Fixed	Oral	300mg to 500mg	300mg to 500mg	NA
Ose (1992)	NA	NA	2	NA	Major depressive episode	4 weeks	Placebo	33	18	50 (median)	30-72 (range)	Fixed	Oral	NA	NA	NA
Parnetti (1993)	Italy	Gruppo Sanofi	2	Secondary/Tertiary Care	Prolonged depressive reaction	12 weeks	Minapramine	63	36	71.599999999999895	6.5	Fixed	Oral	200mg	200mg	200mg
Parnetti (1993)	Italy	Gruppo Sanofi	2	Secondary/Tertiary Care	Prolonged depressive reaction	12 weeks	Placebo	67	47	71.3	6.6	Fixed	Oral	NA	NA	NA
Quitkin (1990)	USA	*MH; NHCRC	2	NA	Major, minor, or intermittent depression	6 weeks	Phenelzine	33	NA	38.9	NA	Fixed	Oral	90mg	45mg to 90mg	NA
Quitkin (1990)	USA	*MH; NHCRC	2	NA	Major, minor, or intermittent depression	6 weeks	Placebo	34	NA	30.1	NA	Fixed	Oral	NA	NA	NA
Raft (1981)	USA	*H	2	Secondary/Tertiary Care	Depression	5 weeks	Phenelzine	NA	NA	NA	NA	Fixed	Oral	90mg	30mg to 90mg	90mg
Raft (1981)	USA	*H	2	Secondary/Tertiary Care	Depression	5 weeks	Placebo	NA	NA	NA	NA	Fixed	Oral	NA	NA	NA
Rampello (1991)	Italy	NA	2	Secondary/Tertiary Care	Primary major u*polar depression or bipolar affective disorder depressed	6 weeks	Minaprine	10	NA	NA	NA	Fixed	Oral	100mg	100mg to 200mg	NA
Rampello (1991)	Italy	NA	2	Secondary/Tertiary Care	Primary major u*polar depression or bipolar affective disorder depressed	6 weeks	Placebo	10	NA	NA	NA	Fixed	Oral	NA	NA	NA
Raskin (1972)	USA	*MH	2	Secondary/Tertiary Care	Depression	5 weeks	Placebo	111	NA	NA	NA	Fixed	Oral	NA	NA	NA
Raskin (1972)	USA	*MH	2	Secondary/Tertiary Care	Depression	5 weeks	Phenelzine	110	72	37 (median)	NA	Fixed	Oral	45mg	22.5mg to 45mg	NA
Ravaris (1976)	NA	Public Health Service; Warner Lambert Research Institute	3	Primary care	Depression	6 weeks	Phenelzine 60mg	21	NA	43.1	15.12	NA	Oral	60mg	60mg	NA
Ravaris (1976)	NA	Public Health Service; Warner Lambert Research Institute	3	Primary care	Depression	6 weeks	Phenelzine 30mg	21	NA	41.2	16.5	Fixed	Oral	30mg	30mg	NA
Ravaris (1976)	NA	Public Health Service; Warner Lambert Research Institute	3	Primary care	Depression	6 weeks	Placebo	21	NA	38.9	10.1	Fixed	Oral	NA	NA	NA
Reimherr (1998)	USA	Glaxo Wellcome Inc.	3	NA	Major depression	8 weeks	Placebo	121	69	40.200000000000003	12.2	Fixed	Oral	NA	NA	NA
Reimherr (1998)	USA	Glaxo Wellcome Inc.	3	NA	Major depression	8 weeks	Bupropion SR 150mg	121	86	38.299999999999997	11	Fixed	Oral	150mg	150mg	NA
Reimherr (1998)	USA	Glaxo Wellcome Inc.	3	NA	Major depression	8 weeks	Bupropion SR 300mg	120	92	38.6	10.7	Fixed	Oral	300mg	300mg	NA
Rickels (1970)	USA	Public Health Service	2	Community, Primary care, Secondary/Tertiary Care	Moderate depression	4 weeks	Methylphenidate	NA	NA	NA	NA	Fixed	Oral	15mg	15mg	NA
Rickels (1970)	USA	Public Health Service	2	Community, Primary care, Secondary/Tertiary Care	Moderate depression	4 weeks	Placebo	NA	NA	NA	NA	Fixed	Oral	NA	NA	NA
Riesenberg (2010)	USA	Rexahn Pharmaceuticals	4	NA	Major depression	8 weeks	Placebo	21	11	42.5	10.8	Fixed	Oral	NA	NA	NA
Riesenberg (2010)	USA	Rexahn Pharmaceuticals	4	NA	Major depression	8 weeks	RX-10100 5mg	21	11	44.8	11.9	Fixed	Oral	5mg	5mg	NA
Riesenberg (2010)	USA	Rexahn Pharmaceuticals	4	NA	Major depression	8 weeks	RX-10100 10mg	16	7	42.6	11.97	Fixed	Oral	10mg	10mg	NA
Riesenberg (2010)	USA	Rexahn Pharmaceuticals	4	NA	Major depression	8 weeks	RX-10100 15mg	17	9	39.4	11.27	Fixed	Oral	15mg	15mg	NA
Robin (1958)	UK	NA	2	Secondary/Tertiary Care	Depression	4 weeks	Placebo	23	13	39.5	13.9	Flexible	Oral	NA	NA	NA
Robin (1958)	UK	NA	2	Secondary/Tertiary Care	Depression	4 weeks	Methylphenidate	22	16	37.5	11.5	Flexible	Oral	20mg to 40mg	NA	NA
Rowan (1980)	NA	NA	2	Secondary/Tertiary Care	Depression or mixed anxiety/depression	6 weeks	Phenelzine	NA	NA	NA	NA	Flexible	Oral	45mg to 75mg	NA	NA
Rowan (1980)	NA	NA	2	Secondary/Tertiary Care	Depression or mixed anxiety/depression	6 weeks	Placebo	NA	NA	NA	NA	Fixed	Oral	NA	NA	NA
Tomarken (2004)	USA	Glaxo Wellcome Inc.	2	Community	Major depression	6 weeks	Bupropion SR	10	6	39.4	9.8	Fixed	Oral	300mg to 400mg	100mg to 400mg	NA
Tomarken (2004)	USA	Glaxo Wellcome Inc.	2	Community	Major depression	6 weeks	Placebo	9	6	37.5	7.8	Fixed	Oral	NA	NA	NA
Ucha (1990)	NA	NA	2	NA	Major depression	6 weeks	Placebo	24	13	42.2	15.1	Flexible	Oral	NA	NA	5.6 tabs per day
Ucha (1990)	NA	NA	2	NA	Major depression	6 weeks	Moclobemide	24	16	40.5	15.6	Flexible	Oral	300mg to 600mg	NA	405mg
UK Moclobomide Study Group (1994)	UK	NA	2	NA	Major depressive episode	6 weeks	Placebo	54	NA	NA	NA	Fixed	Oral	NA	NA	NA
UK Moclobomide Study Group (1994)	UK	NA	2	NA	Major depressive episode	6 weeks	Moclobemide	56	NA	NA	NA	Fixed	Oral	450mg	450mg	NA
Versiani (1989)	NA	NA	2	NA	Major depression	6 weeks	Moclobemide	164	124	44	12	Flexible	Oral	300mg to 600mg	NA	NA
Versiani (1989)	NA	NA	2	NA	Major depression	6 weeks	Placebo	162	123	42	12	Flexible	Oral	NA	NA	NA
Versiani (1990)	Brazil	NA	2	NA	Major depression	6 weeks	Moclobemide	25	NA	NA	NA	NA	Oral	600mg	600mg	600mg
Versiani (1990)	Brazil	NA	2	NA	Major depression	6 weeks	Placebo	25	NA	NA	NA	NA	Oral	NA	NA	NA
Versiani (1997)	NA	NA	2	Secondary/Tertiary Care	Dysthymia	6 weeks	Moclobemide	108	73	41	12	Flexible	Oral	75mg to 750mg	75mg to 750mg	633mg
Versiani (1997)	NA	NA	2	Secondary/Tertiary Care	Dysthymia	6 weeks	Placebo	104	71	40	11	Flexible	Oral	NA	NA	NA
White (1984)	USA	NA	2	Secondary/Tertiary Care	Major depression	4 weeks	Tranylcypromine	63	14	38	NA	Flexible	Oral	30mg to 60mg	NA	44.4mg
White (1984)	USA	NA	2	Secondary/Tertiary Care	Major depression	4 weeks	Placebo	59	21	39	NA	Flexible	Oral	NA	NA	NA
Zarate (2006)	NA	NA	2	Secondary/Tertiary Care	Major depression	8 weeks	Memantine	16	9	47.1	12.3	Flexible	Oral	5mg to 20mg	5mg to 20mg	19.4mg
Zarate (2006)	NA	NA	2	Secondary/Tertiary Care	Major depression	8 weeks	Placebo	16	7	46.1	9.4	Flexible	Oral	NA	NA	NA
Zisook (1985)	NA	NA	2	Secondary/Tertiary Care	Major or minor depression	6 weeks	Isocarboxazid	NA	NA	NA	NA	Flexible	Oral	NA to 80mg	NA	39.00mg
Zisook (1985)	NA	NA	2	Secondary/Tertiary Care	Major or minor depression	6 weeks	Placebo	NA	NA	NA	NA	NA	NA	NA	NA	NA

Table 1. characteristics of included studies that reported anhedonia scores. NA = not available

2.3 Description of included studies

We identified 61 eligible studies. The study characteristics for studies that reported anhedonia scores can be found in Table 1 and characteristics of studies that did not report anhedonia can be found in Table 2. Data from studies contributed with at least one outcome with quantitative data (total of 9975 participants), which included adults from multiple countries. The mean age of participants was 42.4 years (range 15 to 72 years), with a mean proportion of 0.58 female participants (range 0 to 0.86). Included studies allocated the participants to treatment lasting between 4 to 12.9 weeks (median, 6 weeks).

Back to top

2.4 Primary outcome: reduction in anhedonia scores at 8 weeks (from 4 to 12 weeks)

Figure X Forest plot for symptoms of anhedonia (primary outcome) comparing pro-dopaminergic interventions vs placebo for individuals with anhedonia at 4-12 weeks (primary timepoint). SMD: standardised mean difference, 95%CI: 95% confidence intervals, SD: standard deviation.

6 studies contributed with data to the meta-analysis with a total of 2076 participants (1140 allocated to pro-dopaminergic interventions, 936 allocated to pill placebo).

The comparative effect of pro-dopaminergic interventions versus placebo showed an effect favouring pro-dopaminergic interventions with a SMD of -0.244 (95%CI from -0.456 to -0.031). The study results presented an I² value of 67.7% (95%CI from 23.4% to 86.4%) and a tau² value of 0.025 (accounting for a 95% prediction interval from -0.74 to 0.252).

2.4.1 Risk of bias

Evidence for the efficacy of pro-dopaminergic interventions vs placebo in improving anhedonia was rated moderate for risk of bias. 50% of the included studies had an overall high risk of bias while the other 50% had moderate risk of bias, primarily due to missing outcome data, issues with outcome measurement, and selective reporting of findings. The extent to which the result was affected by across-study biases is unclear and all included studies were rated at least moderate in domain 5, selection of results. This result was judged to be at moderate risk of bias due to indirectness as while there was no clear indication of indirectness in terms of population, comparator, or outcomes, 80% of the studies measured the same intervention, bupropion.

2.4.2 Sub-group and meta-regression analyses

We did not perform a meta-regression as the total number of studies was below 10.

2.4.3 Sensitivity analyses

We performed a series of random effects network meta-analyses on the MADRS “inability to feel” item (aggregated IPD from 34 studies, 14054 participants). First, we included all the available studies and compared all the antidepressants against placebo.

The comparative effect of buproprion versus placebo was -0.12 (SMD, 95%CI from -0.25 to 0.00; 34 studies, 14054 participants), lower than what we could observe from the retrieved data (random effects pairwise meta-analysis, bupropion versus placebo): -0.22 (SMD, 95%CI from -0.44 to 0.01; 5 studies, 2020 participants).

We also performed a random effects pairwise meta-analysis of buproprion versus placebo based on the aggregated IPD, resulting in estimates comparable to the network meta-analytical model (SMD -0.12, 95%CI from -0.29 to 0.05; 4 studies, 1085 participants).

Finally, we performed a random effects pairwise meta-analysis including aggregate data from both sources (IPD and retrieved as aggregated). As three studies (Hewett 2009 - 87997883, Hewett 2010a - 87997755, Koshino 2013 - 87997374) were available in both sources, we prioritised aggregate IPD over data retrieved as aggregated. The comparative effect of bupropion versus placebo was -0.19 (SMD, 95%CI from -0.33 to 0.04; 6 studies, 2489 participants)

Back to top

2.5 Secondary outcome: Reduction in mean anxiety score at 8 weeks (from 4 to 12 weeks)

Figure X Forest plot for symptoms of anxiety (secondary outcome) comparing pro-dopaminergic interventions vs placebo for individuals with anxiety at 4-12 weeks (primary timepoint). SMD: standardised mean difference, 95%CI: 95% confidence intervals, SD: standard deviation.

11 studies contributed with data to the meta-analysis with a total of 3517 participants (2077 allocated to pro-dopaminergic interventions, 1440 allocated to pill placebo.

The comparative effect of pro-dopaminergic interventions versus placebo showed an effect favouring pro-dopaminergic interventions with a SMD of -0.166 (95%CI from -0.243 to -0.088). The study results presented an I² value of 0% (95%CI from 0% to 60.2%) and a tau² value of 0 (accounting for a 95% prediction interval from -0.251 to -0.08).

2.5.1 Risk of Bias

2.5.2 Sub-group and meta-regression analyses

The table below shows which of the covariates, if any, explain some of the heterogeneity observed in the effect sizes of the effect of pro-dopaminergic interventions on anhedonia symptom severity. We present marginal R_*² based on effect sizes, which measures the proportion of variance explained by including moderators in the model (the % change in the between-studies variance when the covariate is included in the model, in other words the % of the heterogeneity explained by the variable). For anxiety baseline, the regression coefficient (\(\beta\)) is intended per point increase. For age, the regression coefficient (\(\beta\)) is intended per year of age.

Moderator	\(\beta\)	95% CI	Marginal R*2 (%)
Anxiety baseline	0.03	-0.01 to 0.07	88.35
Age	-0.01	-0.04 to 0.01	0.36
Female proportion	-0.78	-2.4 to 0.84	3.04

Back to top

2.6 Secondary outcome: Dropouts due to any reason

Figure X Forest plot for dropouts due to any reason for the comparison of pro-dopaminergic interventions vs placebo at 4-12 weeks. OR: odds ratio, 95%CI: 95% confidence intervals.

50 studies contributed with data to the meta-analysis with a total of 9168 participants (5234 allocated to pro-dopaminergic interventions, 3934 allocated to pill placebo).

The comparative effect of pro-dopaminergic interventions versus placebo showed an effect favouring pro-dopaminergic interventions with an OR of 0.959 (95%CI from 0.782 to 1.177). The study results presented an I² value of 61.7% (95%CI from 48.1% to 71.8%) and a tau² value of 0.24 (accounting for a 95% prediction interval from -1.045 to 0.962).

2.6.1 Risk of bias

2.6.2 Sub-group and meta-regression analyses

The table below shows which of the covariates, if any, explain some of the heterogeneity observed in the effect sizes of the effect of pro-dopaminergic interventions on anhedonia symptom severity. We present marginal R_*² based on effect sizes, which measures the proportion of variance explained by including moderators in the model (the % change in the between-studies variance when the covariate is included in the model, in other words the % of the heterogeneity explained by the variable). For anxiety baseline, the regression coefficient (\(\beta\)) is intended per point increase. For age, the regression coefficient (\(\beta\)) is intended per year of age.

Moderator	\(\beta\)	95% CI	Marginal R*2 (%)
Anxiety baseline	0.01	-0.01 to 0.03	92.99
Age	0	-0.01 to 0.01	0
Female proportion	-0.15	-1.85 to 1.55	0

Back to top

2.7 Secondary outcome: dropouts due to side effects

Figure X Forest plot for dropouts due to adverse events for the comparison of pro-dopaminergic interventions vs placebo at 4-12 weeks. OR: odds ratio, 95%CI: 95% confidence intervals.

41 studies contributed with data to the meta-analysis with a total of 8473 participants (4831 allocated to pro-dopaminergic interventions, 3642 allocated to pill placebo).

The comparative effect of pro-dopaminergic interventions versus placebo showed an effect favouring pro-dopaminergic interventions with an OR of 1.876 (95%CI from 1.407 to 2.501). The study results presented an I² value of 34.8% (95%CI from 4.4% to 55.6%) and a tau² value of 0.229 (accounting for a 95% prediction interval from -1.045 to 1.636).

2.7.1 Risk of bias

2.7.2 Sub-group and meta-regression analyses

The table below shows which of the covariates, if any, explain some of the heterogeneity observed in the effect sizes of the effect of pro-dopaminergic interventions on anhedonia symptom severity. We present marginal R_*² based on effect sizes, which measures the proportion of variance explained by including moderators in the model (the % change in the between-studies variance when the covariate is included in the model, in other words the % of the heterogeneity explained by the variable). For anxiety baseline, the regression coefficient (\(\beta\)) is intended per point increase. For age, the regression coefficient (\(\beta\)) is intended per year of age.

Moderator	\(\beta\)	95% CI	Marginal R*2 (%)
Anxiety baseline	-0.07	-0.15 to 0.01	95.26
Age	-0.02	-0.05 to 0	34.92
Female proportion	-2.77	-4.91 to -0.62	61.89

Back to top

2.8 Secondary outcome: nausea

Figure X Forest plot for nausea for the comparison of pro-dopaminergic interventions vs placebo at 4-12 weeks. OR: odds ratio, 95%CI: 95% confidence intervals.

24 studies contributed with data to the meta-analysis with a total of 6489 participants (3620 allocated to pro-dopaminergic interventions, 2869 allocated to pill placebo).

The comparative effect of pro-dopaminergic interventions versus placebo showed an effect favouring pro-dopaminergic interventions with an OR of 1.456 (95%CI from 1.182 to 0.584). The study results presented an I² value of 27.2% (95%CI from 0% to 55.9%) and a tau² value of 0.064 (accounting for a 95% prediction interval from -0.189 to 0.94).

2.8.1 Risk of bias

2.8.2 Sub-group and meta-regression analyses

The table below shows which of the covariates, if any, explain some of the heterogeneity observed in the effect sizes of the effect of pro-dopaminergic interventions on anhedonia symptom severity. We present marginal R_*² based on effect sizes, which measures the proportion of variance explained by including moderators in the model (the % change in the between-studies variance when the covariate is included in the model, in other words the % of the heterogeneity explained by the variable). For age, the regression coefficient (\(\beta\)) is intended per year of age.

Moderator	\(\beta\)	95% CI	Marginal R*2 (%)
Age	0	-0.02 to 0.02	0
Female proportion	0.09	-1.7 to 1.89	0

Back to top

2.9 Secondary outcome: headache

Figure X Forest plot for headaches for the comparison of pro-dopaminergic interventions vs placebo at 4-12 weeks. OR: odds ratio, 95%CI: 95% confidence intervals.

26 studies contributed with data to the meta-analysis with a total of 6527 participants (3663 allocated to pro-dopaminergic interventions, 2864 allocated to pill placebo).

The comparative effect of pro-dopaminergic interventions versus placebo showed an effect favouring pro-dopaminergic interventions with an OR of 1.16 (95%CI from 1.03 to 1.307). The study results presented an I² value of 0% (95%CI from 0% to 43.2%) and a tau² value of 0 (accounting for a 95% prediction interval from 0.007 to 0.29).

2.9.1 Risk of bias

2.9.2 Sub-group and meta-regression analyses

The table below shows which of the covariates, if any, explain some of the heterogeneity observed in the effect sizes of the effect of pro-dopaminergic interventions on anhedonia symptom severity. We present marginal R_*² based on effect sizes, which measures the proportion of variance explained by including moderators in the model (the % change in the between-studies variance when the covariate is included in the model, in other words the % of the heterogeneity explained by the variable). For age, the regression coefficient (\(\beta\)) is intended per year of age.

Moderator	\(\beta\)	95% CI	Marginal R*2 (%)
Age	-0.01	-0.02 to 0.01	0
Female proportion	0.5	-0.49 to 1.49	0

Back to top

2.10 Secondary outcome: insomnia

Figure X Forest plot for insomnia for the comparison of pro-dopaminergic interventions vs placebo at 4-12 weeks. OR: odds ratio, 95%CI: 95% confidence intervals.

22 studies contributed with data to the meta-analysis with a total of 5875 participants (3253 allocated to pro-dopaminergic interventions, 2622 allocated to pill placebo).

The comparative effect of pro-dopaminergic interventions versus placebo showed an effect favouring pro-dopaminergic interventions with an OR of 1.791 (95%CI from 1.424 to 2.251). The study results presented an I² value of 5.3% (95%CI from 0% to 37.5%) and a tau² value of 0.03 (accounting for a 95% prediction interval from 0.15 to 1.015).

2.10.1 Risk of bias

2.10.2 Sub-group and meta-regression analyses

The table below shows which of the covariates, if any, explain some of the heterogeneity observed in the effect sizes of the effect of pro-dopaminergic interventions on anhedonia symptom severity. We present marginal R_*² based on effect sizes, which measures the proportion of variance explained by including moderators in the model (the % change in the between-studies variance when the covariate is included in the model, in other words the % of the heterogeneity explained by the variable). For age, the regression coefficient (\(\beta\)) is intended per year of age.

Moderator	\(\beta\)	95% CI	Marginal R*2 (%)
Age	-0.01	-0.04 to 0.02	0
Female proportion	-0.31	-2.14 to 1.53	0

Back to top

2.11 Secondary outcome: constipation

Figure X Forest plot for dropouts due to adverse events for the comparison of pro-dopaminergic interventions vs placebo at 8 (4-12) weeks. OR: odds ratio, 95%CI: 95% confidence intervals.

19 studies contributed with data to the meta-analysis with a total of 4818 participants (2708 allocated to pro-dopaminergic interventions, 2110 allocated to pill placebo).

The comparative effect of pro-dopaminergic interventions versus placebo showed an effect favouring pro-dopaminergic interventions with an OR of 1.551 (95%CI from 1.248 to 1.927). The study results presented an I² value of 0% (95%CI from 0% to 48.9%) and a tau² value of 0 (accounting for a 95% prediction interval from 0.182 to 0.695).

There were no significant subgroup differences between participants assigned to different classes of drug.

2.11.1 Risk of bias

2.11.2 Sub-group and meta-regression analyses

The table below shows which of the covariates, if any, explain some of the heterogeneity observed in the effect sizes of the effect of pro-dopaminergic interventions on anhedonia symptom severity. We present marginal R_*² based on effect sizes, which measures the proportion of variance explained by including moderators in the model (the % change in the between-studies variance when the covariate is included in the model, in other words the % of the heterogeneity explained by the variable). For age, the regression coefficient (\(\beta\)) is intended per year of age. For treatment duration, the regression coefficient (\(\beta\)) is intended per increasing number of weeks.

Moderator	\(\beta\)	95% CI	Marginal R*2 (%)
Age	0	-0.02 to 0.03	0
Treatment duration	0.1	-0.01 to 0.21	0
Female proportion	-0.63	-2.32 to 1.06	0

Back to top

2.12 Secondary outcome: dizziness

Figure X Forest plot for dizziness for the comparison of pro-dopaminergic interventions vs placebo at 8 (4-12) weeks. OR: odds ratio, 95%CI: 95% confidence intervals.

22 studies contributed with data to the meta-analysis with a total of 5469 participants (2996 allocated to pro-dopaminergic interventions, 2473 allocated to pill placebo).

The comparative effect of pro-dopaminergic interventions versus placebo showed an effect favouring pro-dopaminergic interventions with an OR of 1.716 (95%CI from 1.322 to 2.227). The study results presented an I² value of 25.8% (95%CI from 0% to 56%) and a tau² value of 0.08 (accounting for a 95% prediction interval from -0.103 to 1.183).

2.12.1 Risk of bias

2.12.2 Sub-group and meta-regression analyses

The table below shows which of the covariates, if any, explain some of the heterogeneity observed in the effect sizes of the effect of pro-dopaminergic interventions on anhedonia symptom severity. We present marginal R_*² based on effect sizes, which measures the proportion of variance explained by including moderators in the model (the % change in the between-studies variance when the covariate is included in the model, in other words the % of the heterogeneity explained by the variable). For age, the regression coefficient (\(\beta\)) is intended per year of age.

Moderator	\(\beta\)	95% CI	Marginal R*2 (%)
Age	-0.01	-0.03 to 0.02	0
Female proportion	-1.62	-3.59 to 0.34	31.08

Back to top

2.13 Secondary outcome: dry mouth

Figure X Forest plot for dry mouth for the comparison of pro-dopaminergic interventions vs placebo at 4-12 weeks. OR: odds ratio, 95%CI: 95% confidence intervals.

24 studies contributed with data to the meta-analysis with a total of 6308 participants (3431 allocated to pro-dopaminergic interventions, 2877 allocated to pill placebo).

The comparative effect of pro-dopaminergic interventions versus placebo showed an effect favouring pro-dopaminergic interventions with an OR of 2.117 (95%CI from 1.679 to 2.67). The study results presented an I² value of 36.1% (95%CI from 0% to 61%) and a tau² value of 0.08 (accounting for a 95% prediction interval from 0.126 to 1.374).

2.13.1 Risk of bias

2.13.2 Sub-group and meta-regression analyses

The table below shows which of the covariates, if any, explain some of the heterogeneity observed in the effect sizes of the effect of pro-dopaminergic interventions on anhedonia symptom severity. We present marginal R_*² based on effect sizes, which measures the proportion of variance explained by including moderators in the model (the % change in the between-studies variance when the covariate is included in the model, in other words the % of the heterogeneity explained by the variable). For age, the regression coefficient (\(\beta\)) is intended per year of age. For treatment duration, the regression coefficient (\(\beta\)) is intended per increasing number of weeks.

Moderator	\(\beta\)	95% CI	Marginal R*2 (%)
Age	0	-0.03 to 0.02	0
Treatment duration	0.11	-0.04 to 0.25	12.55
Female proportion	-2.07	-3.84 to -0.31	55.49

Back to top

2.14 Secondary outcome: vomiting

Figure X Forest plot for vomiting for the comparison of pro-dopaminergic interventions vs placebo at 4-12 weeks. OR: odds ratio, 95%CI: 95% confidence intervals.

5 studies contributed with data to the meta-analysis with a total of 962 participants (614 allocated to pro-dopaminergic interventions, 348 allocated to pill placebo).

The comparative effect of pro-dopaminergic interventions versus placebo showed a comparable effect not excluding the null effect with an OR of 1.898 (95%CI from 0.901 to 1.386). The study results presented an I² value of 2.2% (95%CI from 0% to 79.7%) and a tau² value of 0 (accounting for a 95% prediction interval from -0.204 to 1.485).

2.14.1 Risk of bias

2.14.2 Sub-group and meta-regression analyses

We did not perform a meta-regression as the total number of studies was below 10.

Reporting bias

Back to top

3. Summary of evidence tables

Source of evidence	Summary of the association	Bias due to study limitations (internal validity)	Bias due to reporting bias (external validity)	Bias due to indirectness	Bias due to other reasons
Pro-dopaminergic intervention. vs placebo in depressed patients with symptoms of anhedonia	N=6, n=2079; random effects: SMD= -0.24, 95%CI: -0.46, -0.03, I2=68%, t2=0.025	Moderate risk: 50% of the studies had an overall high risk of bias (due to missing outcome data, and issues with outcome measurement and selective reporting of findings. 50% of studies had a moderate risk of bias.)	Moderate risk: all studies were rated at least some concerns in RoB2 domain 5, selection of results. The impact of the bias on the magnitude and direction of the effects of pro-dopaminergic agonists is unclear.	Moderate risk: 80% of the studies measured the same intervention, bupropion.For outcomes. 50% of studies measured anhedonia using the MEI, 30% using the MADRS anhedonia item and 20% using the IDS-IVR-30/IDS-C-30 Pleasure Scale  No other clear indication of indirectness in terms of population, interventions, and outcomes.	No clear indication of other biases.
Pro-dopaminergic interventions vs placebo in improving anxiety	N=11, n=3517; random effects: SMD=-0.17, 95%CI: -0.24, -0.09, I2=0%, t2 <0.001	Moderate risk: 60% of studies were rated moderate risk of bias while 10% were rated as high risk of bias. This was primarily due to domain 2- deviation from intended interventions.	Moderate risk: 60% of studies were rated moderate risk in domain 5 of RoB2. The impact of the bias on the magnitude and direction of the effects is unclear.	Moderate risk: 70% of studies contributing to the analysis tested bupropion	No clear indication of other biases.
Acceptability of pro-dopaminergic interventions vs placebo	N=50, n=9159; Random effects: OR=0.91, 95%CI: 0.73,  1.14, I2=72% t2=0.334	Low risk: 10% of studies had an overall high risk of bias, primarily due to concerns over outcome measurement, while 32% were rated moderate risk of bias.	Low risk: the impact of bias on the magnitude and direction of the effects of pro-dopaminergic agonists is low.	Low risk: studies included utilised a variety of interventions used in differing populations in a range of settings.	No clear indication of other biases.
Constipation reported for pro-dopaminergic interventions vs placebo	N=19, n=4809; random effects: OR=1.55, 95%CI: 1.25, 1.93, I2=0% t2=<.001	Low risk: 79% of studies were rated as low risk of bias and no studies were rated high risk of bias.	Low risk: the impact of bias on the magnitude and direction of the effects of pro-dopaminergic agonists is low.	Low risk: studies included in the analysis utilised a variety of interventions used in differing populations in a range of settings.	No clear indication of other biases
Dizziness reported for pro-dopaminergic interventions vs placebo	N=22, n=5460, random effects OR=1.72, 95%CI: 1.32, 2.24, I2=26% t2=0.08	Low risk: 59% of studies were rated low risk of bias and only 5% were rated high risk of bias.	Low risk: the impact of bias on the magnitude and direction of the effects of pro-dopaminergic agonists is low.	Low risk: studies included in the analysis utilised a variety of interventions used in differing populations in a range of settings.	No clear indication of other biases
Dry mouth reported for pro-dopaminergic interventions vs placebo	N=24, n=6299, random effects OR=2.12, 95%CI: 1.68, 2.67, I2=36% t2=0.08	Low risk: 75% of studies were rated low risk of bias for RoB2 while only 4% were rated high risk of bias.	Low risk: the impact of bias on the magnitude and direction of the effects of pro-dopaminergic agonists is low.	Low risk: studies included in the analysis utilised a variety of interventions used in differing populations in a range of settings.	No clear indication of other biases
Headache reported for pro-dopaminergic interventions vs placebo	N=26, n=6518, random effects, OR=1.16, 95%CI: 1.03, 1.31, I2=0% t2=<0.001	Low risk: 62% of studies were rated low risk for RoB2 while 27% were rated as moderate risk with scores of ‘some concerns’ spread out across domains in no clear pattern.	Low risk: the impact of bias on the magnitude and direction of the effects of pro-dopaminergic agonists is low.	Low risk: studies included in the analysis utilised a variety of interventions used in differing populations in a range of settings.	No clear indication of other biases
Nausea reported for pro-dopaminergic interventions vs placebo	N=24, n=6480, random effects OR=1.46, 95%CI: 1.18, 1.78, I2=27% t2=0.06	Low risk: 71% of studies were rated low risk for RoB2 while 21% were rated moderate.	Low risk: the impact of bias on the magnitude and direction of the effects of pro-dopaminergic agonists is low.	Low risk: studies included in the analysis utilised a variety of interventions used in differing populations in a range of settings.	No clear indication of other biases
Insomnia reported for pro-dopaminergic interventions vs placebo	N=22, n=5866, random effects OR=1.80, 95%CI: 1.43, 2.25, I2=5% t2=0.03	Low risk: 68% of studies were rated as low risk for RoB2 while 28% were rated as moderate risk.	Low risk: the impact of bias on the magnitude and direction of the effects of pro-dopaminergic agonists is low.	Low risk: studies included in the analysis utilised a variety of interventions used in differing populations in a range of settings.	No clear indication of other biases.
Vomiting reported for pro-dopaminergic interventions vs placebo	N=5, n=962, random effects OR=1.89, 95%CI: 0.90, 4.00, I2=2% t2<0.001	Moderate risk: 80% of studies were rated as moderate risk and 20% as high risk due to concerns in RoB2 domains 3 (missing outcome data) and 4 (measuring the outcome)	Moderate risk: the impact of the bias on the magnitude and direction of the effects of pro-dopaminergic interventions is unclear.	Moderate risk: only 5 studies contributed to the analysis with a relatively small number of participants. A variety of interventions were tested.	No clear indication of other biases.

Back to top

4. Abbreviations

• CI: Confidence Interval

• GALENOS: Global Alliance for Living Evidence on aNxiety depressiOn and pSychosis

• IPD: Individual Participant Data

• OR: Odds Ratio

• N: number of studies

• n: number of participants

• NI: No Information

• SD: Standard Deviation

• SMD: Standard Mean Difference

• REML: Restricted Maximum Likelihood

• RoB2: Risk of Bias 2

• ROB-ME: Risk of Bias for Missing Evidence

5. Software Used

We used R version 4.3.1 (R Core Team 2023) and the following packages; meta (Balduzzi, Rucker, and Schwarzer, 2019); dplyr (Wickham et al, 2023); readxl (Wickham and Bryan, 2023); kableExtra (Zhu, 2024).

Back to top

6. References

• Higgins, J. P., Savović, J., Page, M. J., Elbers, R. G., & Sterne, J. A. (2019). Assessing risk of bias in a randomized trial.  Cochrane handbook for systematic reviews of interventions, 205-228.

• Flemyng, E., Moore, T. H., Boutron, I., Higgins, J. P., Hróbjartsson, A., Nejstgaard, C. H., & Dwan, K. (2023). Using Risk of Bias 2 to assess results from randomised controlled trials: guidance from Cochrane. BMJ Evidence-Based Medicine, 28(4), 260-266.

• Page, M. J., McKenzie, J. E., Bossuyt, P. M., Boutron, I., Hoffmann, T. C., Mulrow, C. D., ... & Moher, D. (2021). The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.  Bmj, 372.

• Page, M. J., Sterne, J. A., Boutron, I., Hróbjartsson, A., Kirkham, J. J., Li, T., ... & Higgins, J. P. (2023). ROB-ME: a tool for assessing risk of bias due to missing evidence in systematic reviews with meta-analysis.  bmj, 383